The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and is involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281,1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases is reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 describes the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title xe2x80x9cNeurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injuryxe2x80x9d (Authors: A. J. Nimmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).xe2x80x9d
The present invention is a compound of formula 
wherein
R1 a) is unsubstituted phenyl or phenyl substituted by at least one substituent selected from the group R1xe2x80x2 consisting of
halogen,
trifluoromethyl,
unsubstituted piperazinyl or piperazinyl substituted by lower alkyl,
morpholinyl,
NH-phenyl,
pyrrolidinyl,
NH(CH2)nxe2x80x94O-lower alkyl,
NRaRb 
NH(CH2)n-cycloalkyl and
NH(CH2)nxe2x80x94NRcRd, or is
b) unsubstituted morpholinyl, or morpholinyl substituted by one or two lower alkyl groups, or is
c) unsubstituted piperazinyl, or piperazinyl substituted in the 4-position by the group R1xe2x80x3 which is selected from the group consisting of
lower alkyl,
cycloalkyl,
phenyl,
benzoxazolyl,
pyridinyl,
pyrimidinyl
pyrazinyl,
(CH2)n-cycloalkyl,
(CH2)n-phenyl,
(CH2)n-hydroxy,
(CH2)nxe2x80x94CF3,
(CH2)nxe2x80x94C(O)-morpholinyl,
(CH2)nxe2x80x94C(O)xe2x80x94N(Re)-phenyl, wherein the phenyl ring is unsubstituted or substituted by a substitutent selected from the group consisting of
lower alkyl, halogen and
(CH2)nxe2x80x94C(O)xe2x80x94NRfRg,
C(O)-phenyl, wherein the phenyl ring is unsubstituted or substituted by a substitutent selected from the group consisting of trifluoromethyl,
C(O)xe2x80x94(CH2)n-phenyl,
C(O)xe2x80x94NRhRi,
C(O)xe2x80x94NRjxe2x80x94(CHRk)n-phenyl,
C(O)-lower alkyl,
C(O)xe2x80x94CF3,
C(O)-cycloalkyl,
C(O)-morpholinyl,
C(O)O-lower alkyl,
C(O)xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRlRm, and
S(O)2-lower alkyl,
or is
d) unsubstituted pyrrolidinyl, or pyrrolidinyl substituted by at least one group R1xe2x80x2xe2x80x3, selected from the group consisting of
halogen,
hydroxy,
xe2x95x90O,
NRnRo,
N(cycloalkyl)2,
N[(CH2)ncycloalkyl]2,
NRpxe2x80x94C(O)-cycloalkyl, and
Oxe2x80x94(CH2)n-cycloalkyl, or is
e) unsubstituted piperidinyl or piperidinyl substituted by at least one group R1xe2x80x3xe2x80x3 in the 3 or 4-position, selected from the group consisting of
hydroxy,
xe2x95x90O,
halogen,
morpholinyl,
NRs-cycloalkyl,
NRtxe2x80x94C(O)-cycloalkyl,
NRuxe2x80x94C(O)-phenyl,
NRvxe2x80x94C(O)xe2x80x94(CH2)n-phenyl, and
Oxe2x80x94(CH2)n-cycloalkyl,
or is
f) thiomorpholinyl, 1-oxo-thiomorpholinyl or 1,1-dioxothiomorpholinyl;
R2 is independently selected from the group consisting of hydrogen, halogen, lower alkyl, xe2x80x94NHxe2x80x94(CH2)nxe2x80x94O-lower alkyl, pyrrolidinyl and morpholinyl;
R3/R4 are independently from each other trifluoromethyl or halogen;
Ra-v are independently selected from the group consisting of hydrogen and lower alkyl;
n is 1, 2, 3 or 4;
m is 0, 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof
In more detail, the compounds of the present invention relate to the following formulae 
wherein m is 0, 1 or 2 and R1xe2x80x2, R2, R3 and R4 are described above, or to 
wherein R is lower alkyl, m is 0, 1 or 2, R2, R3 and R4 have the significances given above, or to 
wherein m is 0, 1 or 2, R1xe2x80x3, R2, R3 and R4 have the significances given above, or to 
wherein m is 0, 1 or 2, R1xe2x80x2xe2x80x3, R2, R3 and R4 have the significances given above, or to 
wherein m is 0, 1 or 2, R1xe2x80x3xe2x80x3, R2, R3 and R4 have the significances given above, or to 
wherein R2, R3 and R4 are described above and m is 0, 1 or 2.
Further encompassed by the present invention is a compound having the formula 
wherein
R1 is unsubstituted phenyl, or phenyl substituted by one or two substituents, selected from the group R1xe2x80x2, consisting of
halogen,
trifluoromethyl,
unsubstituted piperazinyl or piperazinyl substituted by lower alkyl,
morpholinyl,
NH-phenyl,
pyrrolidinyl,
NH(CH2)nxe2x80x94O-lower alkyl,
NRaRb,
NH(CH2)n-cycloalkyl, and xe2x80x94NH(CH2)nxe2x80x94NRcRd, or is
morpholinyl, or is
unsubstituted piperazinyl, or piperazinyl substituted by the group R1xe2x80x3, which is selected from the group consisting of
lower alkyl,
cycloalkyl,
C(O)-phenyl, wherein the phenyl ring is optionally substituted by trifluoromethyl,
(CH2)nxe2x80x94C(O)xe2x80x94NRfRg,
(CH2)n-cycloalkyl,
(CH2)n-phenyl,
C(O)-lower alkyl,
C(O)xe2x80x94CF3,
C(O)-cycloalkyl,
C(O)-morpholinyl,
C(O)xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRlRm, and
(CH2)nxe2x80x94C(O)xe2x80x94N(Re)-(unsubstituted) phenyl or xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94N(Re)-phenyl substituted by
lower alkyl, or is
pyrazinyl, or is
unsubstituted pyrrolidinyl, or pyrrolidinyl substituted by the group R1xe2x80x2xe2x80x3, which is selected from the group consisting of
hydroxy,
xe2x95x90O and
Oxe2x80x94(CH2)n-cycloalkyl, or is
unsubsituted piperidinyl, or piperidinyl substituted by the group R1xe2x80x3xe2x80x3, which is selected from the group consisting of
hydroxy,
Oxe2x80x94(CH2)n-cycloalkyl,
xe2x95x90O and
halogen, or is
thiomorpholinyl, 1-oxo-thiomorpholinyl or 1,1-dioxothiomorpholinyl;
R2 is selected from the group consisting of hydrogen, halogen, lower alkyl, xe2x80x94NHxe2x80x94(CH2)nxe2x80x94O-lower alkyl, pyrrolidinyl and morpholinyl;
Ra,b,c,d,e,f,g,l,m is independently hydrogen or lower alkyl and
n is 1, 2, 3 or 4;
or a pharmaceutically acceptable acid addition salt thereof.
The compound of formula I and pharmaceutically acceptable salts thereof are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The compound of formula I can also be used in form of a prodrug. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add improvements to the value of the present compound in adsorption, pharmacokinetics in distribution and transport to the brain.
The present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, the preparation of the above-mentioned compounds, pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding pharmaceutical compositions.
The present invention includes all racemic compounds of formula I, also including corresponding enantiomers. Most of the enantiomers have been separated from their corresponding racemic compounds. It has been shown that certain individual enantiomers are more active in the test for NK-1 binding than racemic mixtures as described below. The preferred stereochemical position is the cis-position.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
Preferred lower alkyl groups are alkyl groups with 1-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom to the structure.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred are compounds of formula 1A, in which R1xe2x80x2 is hydrogen, bromo, morpholinyl, 4-methyl-piperazinyl or xe2x80x94NH(CH2)2OCH3, for example the following compounds:
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-morpholin-4-yl-phenyl)-3-phenyl-piperidin-1-yl]-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-{4-[4-(4-methyl-piperazin-1-yl)-phenyl]-3-phenyl-piperidin-1-yl}-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-chloro-phenyl)-4-phenyl-piperidin-1-yl]-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone or
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-{4-[4-(2-methoxy-ethylamino)-phenyl]-3-phenyl-piperidin-1-yl}-methanone.
Further preferred are compounds of formula IB, wherein R2 is hydrogen, fluoro or chloro. Examples of such compounds are:
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-chloro-phenyl)-4-morpholin-4-yl-piperidin-1-yl]-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(4-morpholin-4-yl-3-phenyl-piperidin-1-yl)-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-morpholin-4-yl-piperidin-1-yl]-methanone or
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3xe2x80x2-(4-chloro-phenyl)-4-morpholin-4-yl-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl]-methanone.
Further preferred are compounds of formula IC, wherein R1xe2x80x3 is hydrogen, methyl, xe2x80x94C(O)CF3, xe2x80x94(CH2)2OH, xe2x80x94CH2C(O)N(CH3)2, CH2-cyclopropyl, benzyl, xe2x80x94C(O)-cyclopropyl, xe2x80x94C(O)-morpholinyl, pyrazinyl, cyclopropyl or xe2x80x94CH2CONHC6H3(CH3)2, xe2x80x94CH2CONHC6H4F, xe2x80x94C(O)CH2-phenyl, and R2 is hydrogen, methyl, chloro or fluoro.
Examples of such compounds are:
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-methyl-piperazin-1-yl), -3-phenyl-piperidin-1-yl]-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone,
rac-cis-2{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-N,N-dimethyl-acetamide,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropylmethyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-methanone,
rac-cis-[4-(4-benzyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-(3,5-bis-trifluoromethyl-phenyl)-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-methanone,
rac-cis-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-morpholin-4-yl-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-methanone,
rac-cis-2-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-N-(2,6-dimethyl-phenyl)-acetamide,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-phenyl-4-(2,3,5,6-tetrahydro-[1,2xe2x80x2]bipyrazinyl-4-yl)-piperidin-1-yl]-methanone,
(+)-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-methanone,
Rac-cis-2-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-N-(4-fluoro-phenyl)-acetamide,
Rac-cis-1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-2-phenyl-ethanone,
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-piperazin-1-yl-piperidin-1-yl]-methanone,
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropylmethyl-piperazin-1-yl)-3-(4-fluoro-phenyl)-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[3-phenyl-4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-methanone,
(xe2x88x92)-4-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropylmethyl-piperazin-1-yl)-3-p-tolyl-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-3-p-tolyl-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-{4-[4-(morpholine-4-carbonyl)-piperazin-1-yl]-3-p-tolyl-piperidin-1-yl}-methanone,
Rac-cis-1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone,
(xe2x88x92)-1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropyl-piperazin-1-yl)-3-p-tolyl-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-methyl-piperazin-1-yl)-3-p-tolyl-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-chloro-phenyl)-4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropylmethyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-methanone,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-3-phenyl-piperidin-1-yl}-methanone or
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-cyclopropyl-piperazin-1-yl)-3-phenyl-piperidin-1-yl]-methanone.
Further preferred are compounds of formula IE, wherein R1xe2x80x3xe2x80x3 is selected from the group consisting of fluoro, hydroxy, xe2x80x94NHC(O)-cyclopropyl, xe2x80x94NHC(O)CH2-phenyl, xe2x80x94NH-cyclopropyl, xe2x80x94N(CH2)2, xe2x80x94OCH2-cyclopropyl and xe2x95x90O and R2 is hydrogen, chloro or fluoro. Examples of such compounds are:
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(4,4-difluoro-3xe2x80x2-phenyl-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl)-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3xe2x80x2-(4-fluoro-phenyl)-3-hydroxy-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl]-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(4-hydroxy-3xe2x80x2-phenyl-[1,4xe2x80x2] bipiperidinyl-1xe2x80x2-yl)-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(4-cyclopropylmethoxy-3xe2x80x2-phenyl-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl)-methanone,
rac-cis-1xe2x80x2-(3,5-bis-trifluoromethyl-benzoyl)-3xe2x80x2-phenyl-[1,4xe2x80x2]bipiperidinyl-4-one,
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3xe2x80x2-(4-chloro-phenyl)-4-hydroxy-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl]-methanone,
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3xe2x80x2-(4-chloro-phenyl)-4-cyclopropylmethoxy-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl]-methanone,
(3RS,3xe2x80x2RS,4SR)- and (3RS,3xe2x80x2SR,4SR)-cyclopropanecarboxylic acid [1xe2x80x2-(3,5-bis-trifluoromethyl-benzoyl)-3xe2x80x2-(4-fluoro-phenyl)-[1,4xe2x80x2]bipiperidinyl-3-yl]-amide,
(3RS,3xe2x80x2RS,4SR)- and (3RS,3xe2x80x2SR,4SR)-N-[1xe2x80x2-(3,5-bis-trifluoromethyl-benzoyl)-3xe2x80x2-(4-fluoro-phenyl)-[1,4xe2x80x2]bipiperidinyl-3-yl]-2-phenyl-acetamide,
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3xe2x80x2-(4-chloro-phenyl)-4-dimethylamino-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl]-methanone or
Rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3xe2x80x2-(4-chloro-phenyl)-4-cyclopropylamino-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl]-methanone.
Further preferred are compounds of formula ID, wherein R1xe2x80x2xe2x80x3 is selected from the group consisting of hydrogen, hydroxy,
amino, xe2x80x94OCH2-cyclopropyl and xe2x95x90O and R2 is hydrogen, chloro or fluoro. Examples of such compounds are:
(3R,3xe2x80x2R,4R)- and (3S,3xe2x80x2R,4S)-(3,5-bis-trifluoromethyl-phenyl)-[4-(3xe2x80x2-hydroxy-pyrrolidin-1xe2x80x2-yl)-3-phenyl-piperidin-1-yl]-methanone,
(3R,3xe2x80x2R,4R)- and (3S,3xe2x80x2R,4S)-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-3-phenyl-piperidin-1-yl]-methanone,
rac-cis-1-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-pyrrolidin-3-one,
(xe2x88x92)-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-chloro-phenyl)-4-pyrrolidin-1-yl-piperidin-1-yl]-methanone or
(3RS,3xe2x80x2RS,4SR)- and (3RS,3xe2x80x2SR,4SR)-[4-(3-amino-pyrrolidin-1-yl)-3-(4-fluoro-phenyl)-piperidin-1-yl]-(3,5-bis-trifluoromethyl-phenyl)-methanone.
Further preferred are compounds of formula IF, wherein m is 0, 1 or 2 and R2 is hydrogen. Examples of such compounds are:
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-thiomorpholin-4-yl-piperidin-1-yl)-methanone,
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(1-oxo-1l 4-thiomorpholin-4-yl)-3-phenyl-piperidin-1-yl]-methanone or
rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(1,1-dioxo-1l 6-thiomorpholin-4-yl)-3-phenyl-piperidin-1-yl]-methanone.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
reacting a compound of formula 
with a compound of formula 
forming a compound of formula 
wherein R1 is unsubstituted phenyl, or phenyl substituted by halogen, R2, R3 and R4 have the significances given above, hal is halogen and m is 0, 1 or 2,
or
reacting a compound of formula 
with a compound selected from the group of formulae 
debenzylating, and then acylating with a compound of formula III forming give a compound of formulae 
wherein R, R2, R3, R4 and m have the significances given above, or 
wherein R1xe2x80x3, R2, R3, R4 and m have the significances given above, or 
wherein R1xe2x80x2xe2x80x3, R2, R3, R4 and m have the significances given above, or 
wherein R1xe2x80x3xe2x80x3, R2, R3, R4 and m have the significances given above, or 
wherein R2, R3, R4 and m have the significances given above, or aminating a compound of formula 
with an amine derivative of formula
R1xe2x80x2Hxe2x80x83xe2x80x83VI 
forming a compound of formula 
wherein R1xe2x80x2 is piperazinyl, optionally substituted by lower alkyl, morpholinyl, xe2x80x94NH-phenyl, pyrrolidinyl, xe2x80x94NH(CH2)nxe2x80x94O-lower alkyl, xe2x80x94NRfRg, xe2x80x94NH(CH2)n-cycloalkyl or
xe2x80x94NH(CH2)n-NRcRd, and the definitions of R2, R3 and R4 are given above, or eacting a compound of formula 
with a compound of formula
R1xe2x80x3halxe2x80x83xe2x80x83VII 
forming a compound of formula 
wherein the definitions of substituents are given above, or oxidizing a compound of formula 
with Oxone(copyright)
forming a compound of formula 
wherein m is 1 or 2 and R2, R3 and R4 are described above, or alkylating a compound of formula 
with a compound of formula
R5halxe2x80x83xe2x80x83VIII 
to a compound of formula 
wherein R5 is xe2x80x94(CH2)n-cycloalkyl) and R2, R3, R4 and m are described above, or or
oxidizing a compound of formula 
to a compound of formula 
wherein R2, R3, R4 and m are described above, or halogenating a compound of formula 
orming a compound of formula 
and
if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
The following schemes 1-8 and specific examples 1 to 130 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds and were prepared according to methods known in the art. 
R1 is phenyl, optionally substituted by halogen) R2, R3 and R4 are described above, m is 0, 1 or 2 and hal is chloro or bromo.
Starting materials of formula II or their salts are obtained according to known procedures (e.g. Petit, S.; Nallet, J. P.; Guillard, M.; Dreux, J.; Chermat, R.; Poncelet, M.; Bulach, C.; Simon, P.; Fontaine, C.; et al, Eur. J. Med. Chem. 1991, 26, 19-32).
Compounds of formula I are obtained by acylation of a compound of formula II with an acid chloride of formula III in the presence of a base, like triethylamine, in an inert solvent like methylene chloride. 
R2 is described above, m is 0, 1 or 2 and R1xe2x80x2 is piperazinyl, or piperazinyl substituted by lower alkyl, or is morpholinyl, xe2x80x94NH-phenyl, pyrrolidinyl, xe2x80x94NH(CH2)n-O-lower alkyl, xe2x80x94NRaRb,
xe2x80x94NH(CH2)n-cycloalkyl or xe2x80x94NH(CH2)n-NRcRd. Hal is bromo or chloro and m is 0, 1 or 2.
Compounds of formula 1A1 can be obtained by amination of aromatic chlorides or bromides of formula V using an amine of formula VI, like morpholine or N-methylpiperazine, and sodium tert-butoxide, a catalyst like tris(dibenzylideneacetone)dipalladium(O) and a ligand like rac-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl or biphenyl-2-yl-dicyclohexyl-phosphane in an inert solvent like toluene. The method is described in detail in S. Buchwald et al, J. Am. Chem. Soc. 1996, 118, 7215-7218 and J. Am. Chem. Soc. 1998, 120, 9722-9723. 
Starting materials of formula IV are obtained according to literature procedures (e.g. Lindenmann, Adolf; Suess, Rudolf., CH 545288.)
Compounds of formula IB, IC, ID, IE and IF are obtained by the following sequence of reactions:
1. Reductive amination of a ketone of formula IV using the cyclic tertiary amine as described in scheme 3, an activating agent like titanium(IV)isopropoxide and a reducing agent, like sodium cyanoborohydride, in a protic solvent like methanol or ethanol, followed by hydrolysis of the intermediate cyanamide, using sodium hydroxide in ethylenglycol for the preparation of compounds of formula IC1.
2. Protection of the hydrogen atom on the cyclic amine using trifluoroacetic acid anhydride, 4-dimethylaminopyridine and pyridine in methylene chloride (only for the preparation of compounds of formula IC1).
3. Debenzylation with catalytic amounts of 10% Pd/C with hydrogen at 1 atm in methanol at acidic pH, or debenzylation using 1-chloroethyl chloroformate in methylene chloride followed by refluxing in methanol.
4. Acylation with an acid chloride of formula III in the presence of a base like triethylamine in an inert solvent like methylene chloride.
5. Deprotection of the trifluoroacetamide using potassium carbonate in a mixture of methanol and water (for the preparation of compounds of formula IC1 only). 
R2, R3 and R4 and m have the significances given above and hal is chloro or bromo.
Compounds of formula IC are obtained by
alkylating a compound of formula IC1 with an alkyl chloride or alkyl bromide of formula VII in an inert solvent like N,N-dimethylforamide in the presence of a base like potassium carbonate, or
acylating a compound of formula IC1 with an acid chloride of formula R1xe2x80x3 in an inert solvent like methylene chloride in the presence of a base like triethyl amine, or
treating a compound of formula IC1 with an aromatic bromide or chloride of formula VII at an elavated temperature without any solvent. 
R2, R3 and R4 have the significances given above and m is 1 or 2.
Sulfoxides of formula IF (m=1) are obtained by treating a thiomorpholine of formula IF1 with 0.6 eq of potassium peroxymonosulfate (Oxone(copyright), available from E. I. duPont, Wilmington, Del.).
Sulfones of formula IF (m=2) are obtained by treating a thiomorpholine of formula IF1 with an excess of potassium peroxymonosulfate (Oxone(copyright)). 
R2, R3 and R4 have the significances given above and R5 may be, for example, xe2x80x94(CH2)n-cycloalkyl. Hal is chloro or bromo.
Ethers of formula IE2 are obtained by treating an alcohol of formula IE1 with a base like sodium hydride and an alkylating agent like an alkyl bromide or alkyl chloride of formula VIII in an inert solvent like dimethylformamide. 
Rxe2x80x3xe2x80x3 is morpholinyl, xe2x80x94NRnRo, xe2x80x94NRp-cycloalkyl, xe2x80x94NRxe2x80x94C(O)-cycloalkyl, xe2x80x94NRqxe2x80x94C(O)-phenyl or
xe2x80x94NRrxe2x80x94C(O)xe2x80x94(CH2)n-phenyl, Rn,o,p,q,r, R2, R3, R4 and m have the significances given above and hal is preferably fluoro.
Ketone derivatives of formula IE3 are obtained by Swern oxidation of an alcohol of formula IE1 by methods known in the art.
Compounds of formula IE4 are obtained by treating a ketone of formula IE3 with, for example, diethylamino sulfurtrifluoride, in an inert solvent like methylene chloride.
Compounds of formula IE5 are obtained by reductive amination by treating a ketone of formula IE3 with, for example, titanium(IV) isopropoxide and a mixture of ammonium chloride and triethylamine or a primary or secondary amine and consecutively with sodium borohydride or sodium cyanoborohydride or by substitution of an alcohol IE1 with the sequence (a) reaction with methanesulfonyl chloride and triethylamine in dichloromethane, (b) treatment with sodium azide in dimethylformamide (c), reduction of the intermediate azide with hydrogen and a palladium catalyst (d) alkylation or acylation of the free amine. 
The preparation of compounds shown in scheme 8 is carried out in accordance with the preparation of compounds shown in scheme 7.
Rxe2x80x2xe2x80x3 is NRnRo, xe2x80x94N(cycloalkyl)2, xe2x80x94N[(CH2)n-cycloalkyl]2 or xe2x80x94NRpxe2x80x94C(O)-cycloalkyl, Rn,o,p, R2, R3, R4 and m have the significances given above and hal is preferably fluoro.
The salt formation is effected at room temperature in accordance with methods which are known and are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids are formed by these methods. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methane-sulphonates, p-toluenesulphonates and the like are examples of such salts.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 6.70-9.44 for the compounds of formula I of the present invention. The preferred compounds with a pKi greater than 8.5 are shown in table I below:
Furthermore, it has been shown that the compounds of formula I have a good water-solubility as shown in table II below. This advantage of compounds of formula I over other NK-1-related compounds extends the practicability in administration with regard to certain forms of application.
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatin capsules.
Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
The following Examples illustrate the present invention without limiting it. Unless indicated otherwise, all of the compounds were prepared and characterized by the given methods. All temperatures are given in degrees Celsius.